The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50 ≈ 2.5 μM prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50 = 0.36 μM. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50 = 0.13 μM, or about 20-fold the potency of 1.

Notch信号通路参与细胞增殖和分化，并已被公认为是再生组织和癌细胞的有效途径。Notch信号抑制被认为是治疗多种疾病的可行方法，包括结肠直肠癌，胰腺癌，乳腺癌和转移性黑色素瘤。b环化的二氢吡啶FLI-06（1）是Notch通路的抑制剂，其EC50≈2.5μM的发现促使我们筛选了相关类似物的文库。在进行结构活性研究后，确定外消旋化合物7的EC50 = 0.36μM。合成单个对映异构体可提供（+）-7对映异构体，EC50 = 0.13μM，或效力为1的20倍左右。